Identification of minor histocompatibility antigens restricted by HLA alleles common in Japanese
| Project/Area Number |
15591035
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
AKATSUKA Yoshiki Aichi Cancer Center Research Institute, Division of Immunology, Section Head, 腫瘍免疫学部, 室長 (70333391)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | minor histocompatibility antigen / cytotoxic T lymphocyte / adoptive immunotherapy / hematological malignancy |
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| Research Abstract |
Cytotoxic T lymphocytes(CTL) specific for minor histocompatibility antigens(mHAgs) whose tissue expression is limited to hematopoietic cells are useful for immunotherapy of relapsed leukemia/lymphoma following allogeneic hematopoietic cell transplantation(HCT). We have collected peripheral blood samples 26 patients receiving HCT and generated CTL restricted by HLA alleles commonly seen in Japanese population. First we examined the impact of BCL2A1/A24 disparity on clinical outcome using 320 HLA-A24-positive patients receiving HLA-identical HCT.donor pairs. The results indicate the disparity is unlikely to augment GVHD, suggesting this mHAg may be used for immunotherapy against hematological malignancies after HCT. We next attempted to identify a gene encoding HLA-A^*3303 restricted, male specific mHAg using a CTL clone that preferentially lysed hematopoietic cells. Using a panel of Y chromosome deletion mutant LCLs, the gene was narrowed down to Yq11.221. Further studies using RT-PCR,
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minigene expression and CTL recognition, demonstrated that the mHAg was indeed located in the 5'UTR of TMSB4Y gene. Third, identification of mHAg gene(s) encoding HLA-A^*3303 and -A^*3101-restricted mHAgs was conducted. Linkage analysis demonstrated that two CTL clones specific for these mHAgs recognized a similar epitope(s) from a single region, 15q25. A single polymorphic gene, Cathepsin H, was identified by the aid of expression cloning. This gene has three non-synonymous SNPs and the first one controlled the specificity of these CTL clones. HLA-A^*3303-rectricted CTL recognized 10-mer epitope ending Arg while HLA-A^*3101 -rectricted CTL recognized 9-mer epitope ending the same Arg. Substitution of Arg with Gly which is encoded by Ag-negative allele totally abrogated the binding of the peptide. Cathespsin H is not specifically expressed in hematopoietic cells, but its function is tightly correlated with metastasis of cancer cells. Thus we are currently questioning wheather these epitope is useful for immunotherapy against solid tumors. Less
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Report
(3 results)
Research Products
(21 results)
